Throughout the specification, various references to scientific publications are indicated by the use of numbers. The full citations for these scientific publications are located after the Examples section. The disclosures of all publications, patents, patent applications and published patent applications referred to herein are hereby incorporated herein by reference in their entireties.
Malignant transformation of normal to cancer cells requires the acquisition of several oncogenic traits such as uncontrolled cell division, resistance to programmed cell death (apoptosis), invasion and angiogenesis (1). These malignant transformation traits are believed to be the consequence of the accumulation of genetic alterations that result in dysregulated signal transduction circuits (2, 3). Such genetic alterations can simply be point mutations that result in constitutive activation of key signal transducers such as Ras, a GTP/GDP binding GTPase that contributes to 30% of all human cancers (4). Alternatively, these alterations can involve entire genes such as the receptor tyrosine kinases epidermal growth factor receptor (EGFR) and ErbB2 that are found overexpressed in many major human cancers including breast and lung tumors (5, 6). Often such genetic alterations result in constitutive activation of common downstream signal transduction pathways such as the mitogen activated protein (MAP) kinase cascade c-Raf-1, Mek-1, Erk 1/2, p38 and JNK (7, 8). Other pathways involved in uncontrolled proliferation, apoptosis, invasion and angiogenesis also include those mediated by the signal transducer and activator of transcription STAT3 and the serine/threonine kinase Akt (9, 10). Not only have these oncogenic and tumor survival pathways been found constitutively activated in the great majority of human cancers but also their hyperactivation has been associated with poor prognosis and resistance to chemotherapy in cancer patients (11, 12). This has prompted drug discovery efforts targeting receptor tyrosine kinases, for example, Ras, c-Raf-1, Mek, Akt and STAT3, to thwart aberrant signal transduction pathways in tumor cells (13-16).
In normal cells, it is well established that the activation of the kinase Erk 1/2 is regulated by receptor tyrosine kinases such as EGFR and platelet-derived growth factor receptor (PDGFR) via activation of Ras, which in turn activates the Raf-1/Mek-1/Erk 1/2 cascade (17). Because this signal transduction pathway is hyperactivated in many human cancers, inhibitors of receptor tyrosine kinases, Ras, c-Raf-1 and Mek-1 have all been identified and are at various stages of development (18, 19). One of these inhibitors, gefitinib (marketed as Iressa), an EGFR kinase inhibitor, was recently approved by the FDA for the treatment of patients with lung cancer.
More recently, the beta-2-adrenergic receptor (B2AR) stimulation of cyclic AMP (cAMP) has been shown to regulate the activation of Erk 1/2 in normal cells (20, 21). Interestingly, in some normal cells such as cardiac myocytes and bone cells, B2AR stimulation was shown to activate Erk 1/2, whereas in others such as adipocytes and endothelial cells it was shown to inhibit Erk 1/2 activation (21). In tumor cells, however, whether B2AR stimulation results in inhibition of the Raf/Mek/Erk kinase cascade is not known. The present invention provides for methods of treating cancer by inhibiting the Raf/Mek/Erk kinase cascade.